Perfluorooctane sulfonic acid (PFOS) perturbs skeletal muscle oxidative phosphorylation by a different mechanism than liver
Description
We evaluated PFOS metabolic toxicity in skeletal muscle where not much is known and then compared it to liver metabolic toxicity as measured by bioaccumulation, sarcopenia (muscle loss), RIFS (Respirometry in Frozen Samples; OXPHOS in mitochondria), and RNAseq - GO and KEGG. Skeletal muscle is a healthy body’s largest metabolic organ and therefore presents a target for PFOS-induced metabolic toxicity due to its high mitochondrial content. Mice were treated with 0, 1, or 10 mg/kg/day PFOS for 21-days and gastrocnemius and liver collected. We investigated responses of skeletal muscle to PFOS in vivo and compare the responses of skeletal muscle to liver. All mice exhibited a dose-dependent decrease in bodyweight following PFOS treatment; only females were susceptible to a statistically significant loss of skeletal muscle mass. In contrast, liver weight and hepatosomatic index increased in all mice. PFOS showed significant bioaccumulation in skeletal muscle, albeit lower than the liver. Despite lower bioaccumulation, skeletal muscle was highly sensitive to transcriptomic changes with large differences between skeletal muscle and liver. Only 5% of differentially expressed genes were shared between the tissues. Mitochondrial OXPHOS pathways were highly sensitive to PFOS with ETC 1 most sensitive based on GO term and KEGG pathway analysis. OXPHOS was not significantly different via RNAseq/GO/KEGG in liver; instead PPAR transcription and fatty acid metabolism were some of the more sensitive pathways. Mitochondrial activity assays confirmed that complex I and IV capacity in PFOS-treated female skeletal muscle was repressed. In contrast, complex II capacity was repressed by PFOS treatment in liver. These results indicate that skeletal muscle is sensitive to PFOS toxicity and PFOS perturbs different pathways in skeletal muscle than liver.